The goal of this proposal is to develop an [18F] 5HT2AR agonist radioligand for diagnosis, treatment monitoring and drug development for psychiatric disorders using positron emission tomography (PET) imaging. Serotonin2A receptors (5HT2AR) play a significant role in the pathophysiology of psychiatric disorders and neurodegenerative diseases and are also targets for atypical antipsychotics and antidepressants. 5HT2 agonist hallucinogens have shown efficacy as therapeutics in addiction and in the treatment of pain. PET imaging can provide new insights into the biology of psychiatric disorders, determine prognostic and diagnostic information and response to various interventions by providing quantitative predictions about drug performance. Agonist radioligands would allow measurement of the high affinity conformation of receptors that bind to G-proteins and agonist binding is potentially sensitive to intra-synaptic levels of endogenous neurotransmitters. Our in vitro autoradiography studies using the agonist radiotracer [125I]LSD indicated elevated 5HT2 binding in suicides compared to controls, whereas, the antagonist ligand [3H]ketanserin did not detect differences in binding. We performed in vivo imaging studies in baboon and monkey using the 5HT2AR agonist ligand [11C]CIMBI-5 and obtained specific binding in brain (Figure 1). Although [11C]CIMBI-36 showed better target to non-target ratio than [11C]CIMBI-5 in vivo, a significant limitation for its widespread use is that in high receptor density brain regions the tracer has a slow off-rate making quantification and modeling difficult. The short half-life of [11C] does not allow longer imaging duration for achieving equilibrium binding. Therefore, our goal is to develop a 5HT2AR [18F] ligand that allows imaging over longer scan duration thereby facilitating quantitative kinetic studies and accurate modeling. [18F] tracers, with 110 minute half-life, would also enable transport to nearby facilities that lack an onsite cyclotron and thereby allow cost-effective multicenter clinical studies. We identified FECIMBI-36 as a suitable candidate for [18F] radiolabeling due to its high affinity to 5HT2AR (Ki = 1 nM), selectivity, and agonistic properties (Table 2, 40). We optimized a facile method for radiolabeling and synthesized [18F]FECIMBI-36 ([F-18]1) in 25 5% yield, > 95% purity and > 1.5 Ci/mol specific activity (n = 6). We have preliminary data demonstrating the specific binding of [18F]1 using in vitro autoradiography experiments in slide-mounted sections of human prefrontal cortex, hippocampus and choroid plexus post- mortem (Figures 3 & 4, 40). In this application we propose to evaluate [18F]1 in vivo in rats using microPET and conventional dissection methods. Our goals are to establish specificity by pharmacological blocking studies and evaluate the potential of [18F]1 for imaging the 5HT2AR high affinity site conformation in rats in vivo. An [18F] agonist tracer offers the potential for a commercially viable, more sensitive and accurate tool for investigating the role of 5HT2AR systems in neuropsychiatric disorders, and to measure in vivo occupancies of novel drugs under development through PET imaging studies.